SON drives oncogenic RNA splicing in glioblastoma by regulating PTBP1/PTBP2 switching and RBFOX2 activity

• Published in: Nature communications Vol. 12; no. 1; p. 5551
• Main Authors: Kim, Jung-Hyun, Jeong, Kyuho, Li, Jianfeng, Murphy, James M., Vukadin, Lana, Stone, Joshua K., Richard, Alexander, Tran, Johnny, Gillespie, G. Yancey, Flemington, Erik K., Sobol, Robert W., Lim, Ssang-Teak Steve, Ahn, Eun-Young Erin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21-09-2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/106; 13/51; 13/89; 14; 38; 38/109; 38/77; 38/88; 38/90; 42; 631/208/1792; 631/208/69; 631/67/1922; 64; 64/60; Alternative splicing; Brain; Brain cancer; Brain tumors; Cell proliferation; Downstream effects; Exons; Glioblastoma; Glioblastoma multiforme; Humanities and Social Sciences; In vivo methods and tests; multidisciplinary; Ribonucleic acid; RNA; Science; Science (multidisciplinary); Splicing; Splicing factors; Transcription; Tumors; Xenografts; Xenotransplantation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-25892-x

While dysregulation of RNA splicing has been recognized as an emerging target for cancer therapy, the functional significance of RNA splicing and individual splicing factors in brain tumors is poorly understood. Here, we identify SON as a master regulator that activates PTBP1-mediated oncogenic splicing while suppressing RBFOX2-mediated non-oncogenic neuronal splicing in glioblastoma multiforme (GBM). SON is overexpressed in GBM patients and SON knockdown causes failure in intron removal from the PTBP1 transcript, resulting in PTBP1 downregulation and inhibition of its downstream oncogenic splicing. Furthermore, SON forms a complex with hnRNP A2B1 and antagonizes RBFOX2, which leads to skipping of RBFOX2-targeted cassette exons, including the
PTBP2
neuronal exon
. SON
knockdown inhibits proliferation and clonogenicity of GBM cells in vitro and significantly suppresses tumor growth in orthotopic xenografts in vivo. Collectively, our study reveals that SON-mediated RNA splicing is a GBM vulnerability, implicating SON as a potential therapeutic target in brain tumors.
Splicing factor PTBP1 is reported to promote oncogenic functions in glioblastoma (GBM). Here the authors show splicing factor SON upregulates PTBP1 expression while supresses its paralog PTBP2 through alternative splicing and the inhibition of SON reduces GBM stemness and growth.